About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

July 31, 2005

I'd like to recommend the latest issue of Science, which has a multi-part special section on drug discovery. (Problem is, that link will only work if you're a subscriber, and none of the content is outside the wall.)

I'm not just plugging the articles because one of them quotes me, although that was a nice surprise. The section is a well-done, realistic view of what drug research is like, which should be of interest to the journal's readers (who skew academic). Helping to close the often surprisingly large gap between academia and industry is probably a good deed.

I think that researchers on the industrial side usually feel they have more perspective on that issue, since all of us came from university science departments to start with. Of course, we're not a random sample, since we're disproportionately made up of people who high-tailed it out of academia at the first opportunity. At the very least, we have plenty of people who didn't find the life appealing enough to stay.

Of course, anyone who finds the life of a grad student or post-doc wonderfully appealing probably has some kinks in their psychological hose. I'm sure that being a professor is a much better lifestyle. It is, isn't it?

July 28, 2005

I wanted to mention that I've been gradually adding to the archives and category pages over there on the right-hand side of the page. My original blog, Lagniappe, has been difficult to access on the web due to some ancient HTML, so I'm taking the still-relevant posts from there (2002 into early 2003) and putting them into the appropriate categories.

Three dozen or so have been added in the last week or two, and more are coming. I'm fishing everything out of the Internet Archive, so all links are in there, although they're not all guaranteed to still work. (I do have the day job at the Wonder Drug Factory, y'know.) After that I'm going to categorize the Pipeline posts from the pre-Movable Type days, so those will start showing up over there, too. Enjoy (I hope), and keep an eye out for more (semi-)new content.

After presenting some disappointing data at the spring ASCO meeting, Novartis and Schering AG's tyrosine kinase inhibitor for colon cancer (PTK/ZK) looked to be in trouble. The "CONFIRM-1" trial showed no real benefit from using the drug on top of standard chemotherapy, but "CONFIRM-2" was also underway. That one looked for efficacy in patients who had already failed first-line therapy, and the results are now in: no survival benefit. The financial markets weren't happy, but weren't too surprised - that second trial was a tougher one to reach significance in, given the nature of the patient population.

It's a real whimper of an ending for a drug that some were once touted as the next Avastin. Schering AG kept tossing billion-dollar sales projections around for a while there, and kept trying to put the best face on things even as the bad news started coming in. Their earlier press release on the CONFIRM-1 data, for example, is a model of the Power of Positive Thinking, and is worth a look in light of today's announcement.

It started off with the headline "First results from PTK/ZK CONFIRM 1 trial. . .show positive drug effects in advance colorectal cancer." As you read further, you got to a figure of 17% reduction in risk of disease progression for the combination therapy, as opposed to the standard regimen, "as assessed by investigators." "Assessment by central review," however, showed a 12 per cent reduction, which didn't even reach statistical significance. Halfway down the first page, and the wheels have come off completely, but you'd never know it from reading the bold print at the top.

The chances of PTK/ZK reaching the market have to be close to zero. I know that at one point the companies were looking to go into non-small cell lung cancer, but I wouldn't hold out much hope there, either. As usual when a heavily studied drug candidate goes into the trash, I'd like to remind everyone that all the money that Novartis and Schering AG spent on this, and it was surely a lot, is burned up and gone. This was a Phase III failure, about as expensive as it comes. That cost will be reflected in the price of the next things that either company gets to the market, depend on it. They'll have to make it up somewhere; it's the nature of our industry.

As fate would have it, some other negative clinical data came out today. A study in the New England Journal of Medicine has shown, rather definitively, that the popular herbal supplement echinacea seems to have no effect on colds at all. That's rather in contrast to the signage over on the herbal medicine shelves at my local pharmacy, when I think about it.

Ah, but now that this trial has been run, what are the chances of my being able to go to that drug store next week, next month, next year, and see echinacea promoted as being good for colds? Do I hear. . .close to one hundred per cent? Of course! Herbal medicine companies are made of sterner stuff than we are over here in the artificial non-holistic world. They won't let a little thing like lack of efficacy slow them down.

July 27, 2005

Since I was speaking about who might win the first Vioxx trial, I should finish my thoughts. If Merck loses (which they may or may not deserve to), the next question is what sort of damages they should pay out.

It's safe to say that my estimate and that of Mark Lanier, the chief attorney for the plaintiffs, would differ by several orders of magnitude. He would doubtless be overjoyed by, say, a three hundred million dollar award, and would rejoice at the thought of this opening the floodgates for more of the same. I, on the other hand, would be extremely upset at the likely destruction of a great drug company.

What to do? I sometimes think that every prescription in the country should be covered by a blanket waiver, which would go something like this:

"The manufacturer, together with the Food and Drug Administration, have investigated the safety and efficacy of this medication. By allowing it to be dispensed, these parties have agreed that, on the basis of the available data, its use represents a reasonable return in beneficial health effects, as compared to the concomitant risks.

By accepting this medication, you the consumer agree that you have been informed that these risks are real, and that they can include, but are not necessarily limited to, those detailed in the package insert. Although medications are tested in humans before regulatory approval, no such clinical trials can possibly predict what may occur when a new drug is widely dispensed in the general population. Use of this medication will define you as a participant in the post-approval study of this drug, and may affect your legal status to obtain redress from any real or perceived injuries associated with its use.

Should any criminal activity be shown to have occurred during the development or approval of this drug, including but not limited to the presentation of fraudulent data or the witholding of relevant information, this waiver may be voided in whole or in part."

July 26, 2005

I haven't been talking about the Merck-Vioxx trial, but people are asking me how I think the it's is going. Unfortunately, I have no idea. And, I'd think that most of the people commenting on it in the press have no idea, either, when you get right down to it. All I know about the testimony is what I read in the media, and I'm not willing to accept that data as good enough to use.

The daily reports coming out of Texas are probably about as misleading as a round-by-round commentary of a boxing match. Anyone reporting this story is looking for exciting news, a big quote, a damaging revelation or slip-up. That's what will get the most play, and if there wasn't anything in those categories on a given day, the next best thing will do. A trial is a natural fit for the narrative instincts of most reporters, and that's what the readers expect to see, too.

The similarities to the reporting of an electoral campaign or confirmation hearing should be kept in mind, and a political scandal is the perfect example of the form. Punch! Counterpunch! Attack from the right! Feint from the left! A steady delivery of reasonably sized news chunks keeps the story moving along, the viewers tuned in, and the readers buying papers. Never ignore narrative bias; you're soaking in it.

But, unlike a boxing match, we don't know who's ahead on points so far in the Merck trial. The jury will be influenced by the facts presented to them, but also how they were presented and by whom. All of this will be layered on top of what they already know and the opinions that they already have. I don't presume to know what's going through their minds, because even if I were sitting there in the courtroom with them, I'd surely have a different perspective on the whole matter. If I had to guess, I'd say that Merck has a reasonable chance of getting out of this one. But I'm not putting any money down on that opinion. Merck's got enough on the table for everyone.

Well, fine, you say - but who should win? Grudgingly, I have to admit that I don't know the answer to that one, either. The details of the death in this case aren't all out yet, and I'm not a pathologist. And the details of Merck's internal knowledge and subsequent marketing decisions aren't all out yet, either. I think that their problem was believing what they wanted to believe (a tendency never to be underestimated), but it could end up looking worse (or better) than that.

However, it does seem clear that COX-2 inhibitors have caused, or at least contributed to, some deaths. Balancing those against the benefits they may have had for a much larger group of people is a very difficult calculation, but it's one that you'd have to make before coming to a final judgment on the whole class. The FDA has, of course, decided to leave the drugs on the market, so you know where they finally came down.

But the overmarketing of the drugs (by everyone, not just Merck) is, in the end, how we got into this situation. If COX-2 inhibitors had been prescribed mostly to people who had demonstrated an intolerance to the existing drugs, I doubt if any excess deaths would have been noticeable even had they occurred. (But if that had been the expected market, how many companies would have entered the field at all?)

Things have come to the point where many companies have made the decision not to get involved in huge marketing battles over blockbuster drugs. They're trying to put together a business out of more specialized drugs in less competitive areas, or where there's less direct-to-consumer marketing (which is quite expensive.) The pendulum, perhaps, is swinging back.

July 25, 2005

I recently saw a demonstration of a gizmothat promises to make catalytic hydrogenation easier. If it works, it's about time. This is an ancient reaction (the standard apparatus is pretty much unchanged since the 1920s), but it's still extremely useful. But nobody likes to run the darn things.

For the non-chemists in the crowd, the idea is that hydrogen gets added to a bond (or bonds) in your molecule. So a carbon-carbon double bond gets reduced to a single bond, for example, or a triple bond to a double. (Unless you're careful, though, that triple bond is going to go all the way down without stopping.) You can even reduce aromatic rings down to their saturated counterparts, which was the very reaction I was speaking about the other day (taken a hexagon-with-a-circle drawing down to a plain hexagon.)

And it doesn't have to be C-C bonds that you reduce. N-O bonds are particularly labile to the reaction, so nitro groups get turned into amines, among other things. And some single bonds, especially those near aromatic rings, can just get completely cleaved, which is the basis for a lot of protecting group chemistry that people use to tape down reactive parts of their molecules for a while.

To do all these neat things, you need a metal catalyst, whose efficacy correlates nicely with their cost. Platinum, for example, is a fine one. Palladium, its blood relation, is very widely used. Nickel, rhodium, and iridium have their uses, and from there you go off into some real esoterica. These things are sometimes used just as fine metal powders, but often they're furnished as a fine dispersion on some sort of solid support - powdered charcoal or alumina, for example. Good ol' 5 per cent palladium on carbon is probably the most often used hydrogenation catalyst in organic chemistry.

You might get the impression from all these variations that the field is lacking in rigor. You would be very correct indeed. Tom Goodwin, my undergraduate organic chemistry professor, accurately described it as "witchcraft." The real atom-by-atom mechanism of the reaction is known in broad detail, but many key things are still obscure. Hydrogenations can vary not only according to the substrate molecule and the metal, but according to its solid support (and its loading on it), the solvent used in the reaction, the temperature, the pressure of the hydrogen gas in the vessel, and the source of the hydrogen itself.

It's that hydrogen gas that causes the uneasy feelings about the reaction. Hydrognations have been responsible for untold minor fires in labs all over the world, and once in a while a major one. Hydrogen is famously flammable itself, but there are other problems. Once the metal catalysts are saturated with the gas, they often glow red-hot on exposure to air, which is not so good when you have lots of organic solvent around. The "Raney nickel" catalyst comes already soaking in hydrogen, and a classic way of seeing if it's still good is to wipe some of the wet powder on a paper towel. If it bursts into flame when it dries, it's fine.

I've instantly singed the hair from the upper joints of my fingers through misjudgment of these little details. (Another hard-to-forget experience with hydrogenation apparatus is here. If this contraption works as advertised, perhaps my nerves will have one less thing to jangle them.

In the drug industry, we tend to look down a bit at academia's attempts at pharmaceutical research. We don't go out of our way to hire people with university degrees in medicinal chemistry, for example, which you'd think would be a perfect fit. (Here's why.) And we're always insinuating that the professoriat just doesn't understand what it takes to develop a drug, and what kind of timelines have to be met. I've made a number of comments like that here, and I'll surely make some more.

But I have to admit that it's not always true. There are a few drugs that have come out of academic research, although in all the cases I'm aware of, much of the expensive heavy lifting was done after signing a deal with a pharma or biotech company. (Scroll down to the September 2004 posts herefor more ranting than you may need on the "all drugs come from academic research anyway, right?" position.)

One notable success story has been the antiretroviral Emtriva (emtricitabine), a nucleoside mimic that acts as a reverse transcriptase inhibitor. It was discovered in a longstanding program to find new antiviral agents at Emory, with the chemistry coming from Prof. Dennis Liotta and his group. (Personal disclosure: I nearly went to Emory for grad school to work in Liotta's group, and was strongly considering doing a post-doc with him afterwards. And I've attended his Gulf Coast Chemistry Conference a couple of times as well.)

I mention all these connections, I guess, because word comes now that Emory has cut a deal cashing in all future royalties for a record-setting $525 million dollars. They're selling 65% of the royalty stream to Gilead, the company that markets Emtriva (the orginal deal was done with Triangle Pharmaceutical, a firm of Burroughs Wellcome refugees later bought by Gilead), and 35% to VC firm Royalty Pharma. And the deal provides that the University itself gets 60% of that, with the rest to be split between Liotta, Raymond Shinazi (on the medical side), and former Emory researcher Woo-Baeg-Choi.

That is 210 million dollars to be split between the three of them. My heartiest congratulations, from down here on the floor where I'm fanning myself. I can tell you that if I come up with a winning drug here in industry, I'll likely get promoted, and may well even see a bonus. But I will most definitely not see any seventy million dollars. Maybe this academic model for drug discovery has something to it after all. . .

July 21, 2005

So, you're wondering, no doubt, if steely-eyed drug discoverers, those hardy scientific pioneers, are perhaps just the tiniest bit embarrassed when their company issues a press-release like this one?

"Schering-Plough Plans Tutti-Frutti Clarinex", runs the headline. And the answer is, yes, the research divisions generally cringe at the sight of such marketing brainstorms. That's partly because these line extensions always seem a little beneath everyone's dignity ("Now with the great taste of fish!") And it's partly because the drug discovery folks realize that if they'd come up with more new things for Marketing to sell, their companies wouldn't be reduced to this kind of thing.

The devil does indeed find work for idle hands. And those hands are capable of most anything, even. . .tutti-frutti Clarinex.

July 20, 2005

"Something that comes up every now and then when discussing IP issues and freedom to operate is to dream about having a ship or island that's in international waters and free from all international patent laws. Obviously you can't sell things made on the ship in any country that are covered by composition of matter, but any patented processes could be performed there, and people who wanted to use patented matter could go there for treatment. . ."

He passes along a link to this blog, which is discussing this news item. There's an outfit called SeaCode that plans to anchor a ship just outside US waters off Los Angeles, stock it full of coders, and crank out software at outsourcing prices (while staying in the same time zone as Silicon Valley.)

And the thing is, something similar to SP's idea already goes on. Multinational US companies, for example, run assays in Europe if they're blocked by a US patent. And there's Panlabs, part of MDS Pharma Services. They run all sorts of assays for you, hundreds of the things, and some of them are clearly covered by other people's patents in some of their customer service zones. But they have that taken care of by being all over the place, including some spots that many assay patents don't necessarily reach (Taipei, to pick a big example, where their main assay lab is.)

The difference between this sort of thing and SeaCode is that the assay companies aren't primarily driven by labor costs. Larger companies use them because they don't keep all these screens running all the time, and it's a convenient one-stop way to profile interesting compounds. (Including, of course, some assays that you probably just can't run.) But they're not particularly cheap, although when you work out the cost of establishing a new assay of your own, they don't look as bad. . .

July 19, 2005

Physics prof Chad Orzel published a guide last week to surviving organic chemistry seminars. (I can understand that that's a particularly high priority for people who don't know any organic chemistry and have to sit through these things, actually.) He provides what is, for an organic chemist like me, an interesting man-from-Mars viewpoint:

"Stage Two: "Here's the stuff we start with." This will include a couple of diagrams showing different arrangements of hexagons. The jargon will get pretty thick, here, but almost all the strange words will be names of different parts and sub-parts of molecules. . .

Stage Three: "Here are the steps in the process." This will include at least one slide showing multiple diagrams of hexagons, with arrows between them. The jargon will again be pretty thick, but here, all the strange words will refer to methods of sticking pieces of molecules together. . ."

Ah, but are these the hexagons with little circles in the middle of them, or the plain ones? Very different, those guys are. Since he didn't mention dashed and wedged bonds, I'll assume it's the former. Rarely will those arrows point from one kind to the other, by the way. You can turn the circle-inside guys to the uncircled kind and vice versa, but it takes some real hammer-and-tongs reactions to do it. I haven't run one of those for over twenty years now, to give you the idea.

Keep in mind that we use pentagons and heptagons, too, but you won't see many circles inside them (although it's possible, especially if you're sitting through an organometallic chemistry talk.) Squares are rare, but triangles can represent a group that I've always liked, and that I have a reputation for introducing into my lab's molecules.

Once you've staggered through the talk, there's the problem of questions at the end, naturally. Orzel's advice:

"If you absolutely need to ask a question, remember that the crucial figure of merit for these talks is the "yield," which basically means "How much product do you get for a given volume of reactant?" If the speaker hasn't mentioned the yield specifically, you can't go wrong asking "What's the yield like?"

If they have stated the yield, ask "How does the yield stack up against other methods of producing this stuff?"

If they have stated the yield, and compared it to existing methods, and you still feel a need to ask a question, ask about the solvent peaks/ blobs/ pencil marks.

Questions of the form "Why are you trying to make this stuff in the first place?" are usually considered unsporting. . ."

Ay, that's for sure. I'm glad no one asked me that last one during my PhD defense, because by that time I'd begun to realize that most of my possible answers were pretty weak. I sure don't think I'd have been able to get them out with the tone of conviction I'd have had three years before. As I told people near the end - no, not my examining committee, what do you take me for - "The world doesn't need another synthesis of this molecule. But I do."

But I'd ask Chad to take heart - I don't hear many physics presentations, but I do have to sit through some pretty gritty molecular biology talks from time to time. I can deal with those, for the most part, except (as I've mentioned) for the sneaking suspicion that I've been seeing the same electrophoresis gel since 1987.

And, frankly, I'm not all that good at sitting through talks in my own field. My tolerance of uninteresting work has not improved over the years, and my definition of "uninteresting work" is gradually becoming more inclusive. It's to the point that some of my colleagues give me the raised eyebrow when I actually show up at a seminar. I feel, in other words, Chad's pain.

July 18, 2005

One of the many interesting points that came up in the comments to my Brazil posts was from a reader who wondered how easy it was for someone to get the structure (and synthetic route) for a marketed medicine. In other words, what are the barriers to ripping off someone's patent?

And as some of my industry readers correctly told him, those barriers are few indeed. The structure of an FDA-approved drug is a matter of public record, and is included in the required package insert with every prescription. And the patents are required to tell you how to make it. In fact, in almost every case, the only reason that a patented drug isn't copied is patent law itself. That gets right to the concept of what a patent is: in return for a defined period of monopoly, the patent holder agrees to disclose all the relevant facts about the invention.

For a drug industry patent, that means that the generic structure of the claimed compounds is in there, as well as at least the names and some physical properties of all the specifically exemplified compounds. (Chemical names are systematic enough to determine the structure, but most patents have the structural drawings, anyway.) General chemical routes are laid out, along with specific examples that get right down to the bench-level details. A chemical matter patent, in order to be valid, has to teach a reader of ordinary skill in the art how to make the claimed compounds. If it doesn't, it shouldn't have been granted, and can be invalidated. (This isn't merely an academic point - part of the reason that Bayer got ciprofloxacin (Cipro) from out of a SmithKline patent claim was that the routes shown couldn't make the compound.)

Now, there's still a bit of wiggle room. You don't have to list biological activities of all the compounds that you exemplify, although it does build a stronger case. If you're claiming a particular biological activity, you have to show how you assayed for it, but often you'll see the detailed assay procedure along with a note to the effect that "the compounds of this invention were tested according to this protocol and showed inhibition constants of between 0.01 and 10 micromolar."

That satisfies the legal requirements, but it doesn't satisfy the reader very much, which is the whole idea. There's a constant guessing game when your competitors aren't on the market yet and haven't disclosed much about their clinical trials. Ten nanomolar to 10 micromolar is a wide range of activity, from the very interesting to the surely useless, and there's often no way of finding out which compounds were the best.

You can narrow things down by some detective work, though. Looking over the specific examples in the patent(s) can tell you what chemical classes they spent the most time on, and what regions of the molecule seemed to be most important. If your competitor has gone to the trouble of filing a process patent (covering a specific route to make certain compounds, as well as the compounds themselves), then you can be pretty sure that they're interested in that class. And looking at the specific examples in the patents will sometimes show an interesting pattern: ten, twenty, fifty compounds are all shown being prepared in 20-milligram amounts, followed by one that's made on a ten-gram scale. Aha!

Now, in the absence of a process patent, you're still not guaranteed that the method shown in the original patent is the one that they're using to make it on large scale. Actually, you're more like guaranteed that it's not. Ten grams is one thing, but a thousand-kilo route is quite another. A patent is required to disclose the best mode to realize the invention that you know of at the time of filing, and that's generally before the process chemists have had time to work on the synthetic route. (Patent cases have hinged on the timing of those steps.)

But a good process group can usually take the structure and the patent route and work something out, for a tiny fraction of the time and effort it took to find the compound the first time and get it tested and approved. And if it weren't illegal, that's exactly what people would do. And then who would go to the trouble of being first?

July 17, 2005

It's no wonder that there's still so much argument over autism and vaccines. Paranoia is an endlessly renewable resource - big glowing hunks of it are always being dug out of the ground and put to use. For an unfortunately typical example, take a look at this piece from the New York Times. Some fifteen years ago, studies were carried out in New York to determine the safety and efficacy of pediatric doses of the existing HIV medications:

The controversy extends back to a bleak period in New York City history when well over a hundred children a year were dying of AIDS, most under the age of 5. As many as one in every five children infected with H.I.V. were dead by 2, doctors now say; up to 50 percent were dead by 4.

There were no AIDS drugs approved for children in those years. The first AIDS drug, AZT, was approved for adults in 1987. Babies were being abandoned in hospitals, their mothers unable to care for them and with no foster homes available. About 40 percent of the children with H.I.V. were in foster care.

As a result, pediatricians began pressing pharmaceutical companies to let them try drugs shown to work in adults. . .

. . .One center that took part in the trials was a small boarding home for H.I.V.-infected foster children called Incarnation Children's Center, the brainchild of Dr. Stephen W. Nicholas, now director of pediatrics at Harlem Hospital Center. With as many as 24 infected children abandoned in the hospital in 1988, the idea of finding them a home outside the hospital came to him after a young patient greeted him with, "Hi, Daddy."

Working with Columbia University and the Catholic Archdiocese of New York, Dr. Nicholas became the medical director of Incarnation, on Audubon Avenue in Washington Heights, which opened in 1989 and added an outpatient clinic in 1992. Foster children there and elsewhere were enrolled in trials - at first, trials of single drugs like AZT, and later, of multiple-drug cocktails and protease inhibitors, which by 1996 were helping turn AIDS into a manageable, if still chronic, disease.

For his trouble, Dr. Nicholas became the focus of attention from one Liam Scheff, who published a screed 18 months ago on Indymedia (and didn't I groan when I saw that phrase in the article) accusing the Incarnacion facility of forcing poisonous drugs down the throats of innocent children, killing who knows how many in the process, et cetera, et cetera. I should mention that Scheff doesn't think that HIV is likely to be the cause of AIDS, doesn't think that the drugs against it necessarily have done any good, and so on - just so you all know where he's coming from.

Witness now how avalanches start: That Indymedia piece set off a group called the Alliance for Human Research Protection, whose publicity got the New York Post going, which led to a BBC-financed film ("The New York Experiment - Guinea Pig Kids"), which ignited the activists at a Brooklyn-based group that seeks reparations for slavery and whose leader claims (with no apparent evidence) that many of the children didn't even have HIV:

What we know already," he said, "is that 98 percent of the children experimented on were black and Latino and that the fundamental basis of why they chose those kids was racism. They have the arrogance to say it was for their own good, but we know it was racism."

That brought a couple of city councilmen into camera range, and things have continued to deteriorate. At this point, what really happened in the late 1980s doesn't seem to matter much, but for the record:

"Pediatricians involved in the trials say they are mystified by the onslaught. While powerful drugs do have side effects, many said, they remembered no fatal reactions. At Incarnation, Dr. Nicholas said, no child had died of a reaction and "no child ever had an unexpected side effect."

He said that, with one exception, no children had been included in the trials without "absolute proof" by advanced testing methods that they were infected and not simply carrying their mother's antibodies. He said the exception was a trial that proved that by giving AZT to pregnant, infected women and then to their newborns in the first six weeks of life it was possible to sharply reduce the rate of H.I.V. transmission from mother to child. He called that study "the most important clinical trial in the history of AIDS."

Well, yeah, fine - but what about the secret experiments? Evil corporations and secretive government agencies? Racist plots and toxic drugs administered by sinister doctors? What about the good stuff? Hasn't Dr. Nicholas watched any TV, seen any hit movies? Doesn't he know how this country really works?

My heart goes out to him, actually. From all I can tell, he has done the world a real service, and saved more children than could we can count from awful, lingering deaths. For this, he and his co-workers get the Mengele/Tuskegee treatment from publicity hounds and people who've rotted their brains reading Indymedia. What a reward.

July 9, 2005

Just wanted to let everyone know that posting will be light to nonexistent this week. I'll pop up if something big happens, but otherwise I'm going to be taking it easy for a few days. The regular schedule of fist-waving and table-pounding will resume a week from Monday, though, never fear.

July 7, 2005

I didn't plan on becoming the defender of Abbott's pricing decisions, particularly after that Norvir business in 2004, which I though reflected poorly on them. But these are special circumstances. Since we're on the subject of Brazil and its compulsory licensing threat, I thought it would be worth going to the source. Here, then, is the statement of Brazil's Minister of Health on the matter, dated June 27th. There are some interesting features in it that I'd like to highlight (emphasis added):

"This stage may come to represent the first step for introducing a new phase in our local ARV production. An additional target is to support our national manufacturing industry in this respect, as we are totally committed in maintaining high quality in the medicines available in the public health services.

The Brazilian law allows compulsory licensing in cases of public interest or emergency situations. These are related to issues that involve health, nutrition, protecting the environment, and the technological or sociological development of the country."

Now, much of the rest of Dr. Humberto Costa's statement emphasizes pricing. But I find the industrial-policy aspects rather troubling. How much of this decision is predicated on economic nationalism? We can argue about to what extent Abbott should forgo Kaletra profits in order to help poor Brazilians who are infected with HIV. But should they forgo profits in order to develop the Brazilian generics industry? Here's some more from Dr. Costa:

"In spite of being successful in reducing prices over the period, Brazil still pays exorbitant and unacceptable prices even from the point of view of the full application of capitalist principles."

Wow, even from the point of view of capitalism and everything. . .we've gone about as far as we can go, I guess. How annoying that the antiretroviral drugs have pretty much all come from people who hoped to earn back the immense cost of their development. All I can say to Dr. Costa is: if you think the prices you're paying are unacceptable, you should see what other people have to pay to make up for yours.

And here comes some more capitalism, so get braced: if you go ahead and confiscate someone else's intellectual property, companies will have to factor the chance of that happening again into their future development costs and pricing decisions. And no, in case you're wondering, that will not make prices go down, and it will not make people eager to do more business in Brazil. Not to worry, though: if countries around the world follow your example and seize whatever drugs suit them, eventually there won't be many drugs to seize.

July 6, 2005

Just how much should an anti-HIV drug cost? What if you're selling it in a place where most of the patients can't afford it? These questions have been fought out in Africa and other parts of the developing world over the last few years (and the stagnating world, too, unfortunately.) Now Brazil may be making good on a threat of outright patent confiscation.

The Brazilian government is unhappy with the price of Abbott's combination therapy, Kaletra (PDF), which they already pay just over $100 million per year for. Mind you, that's the lowest price in the world outside Africa. Online pharmacies claim that the average US retail for Kaletra tablets is about $4.06 each, and they offer it at about $3.60. Brazil's paying $1.17, and they're saying that they'll issue a compulsory license if the price doesn't come down to 68 cents.

They've threatened to do this before, but have never come this close to following through. The worry for Abbott is that once the Brazilian generic companies start making the stuff, it'll end up all over the rest of the world at a base of $0.68/tablet. And where do you think demand for it will be strongest? In the countries where it's already the most expensive, which Abbott is counting on for their profits.

Opinions vary a bit, as you'd figure. You can find no shortage of activists cheering the Brazilians on. To wit, from the AP article linked above:

"We are the hostages of these companies, and compulsory licensing is a defense against the abuse of monopolies," said Jorge Beloqui, the leader of a Sao Paulo-based AIDS support group.
Beloqui, a university math professor, has taken 30,000 anti-AIDS pills provided free by the government since 1991. If Brazil breaks the patent, he says, activists will pressure Brazilian politicians to go a step further and let its generic drug makers produce much more of Abbott's drug so it can be shipped around the world to needy patients.
"These medicines are essential to the world, and I think Brazil should sell them," he said.

Actually, Prof. Beloqui is the hostage of a retrovirus, but his comments seem pretty representative of the "stick it to The Man!" point of view. Well, speaking for The Man (to crib a line from Tom Wolfe), I have to say that Brazil seems to be playing to the galleries here. There are accusations that the country is spending less on anti-HIV medications than it did five years ago, and they turned down $40 million in US money not so long ago. There's another problem, too. Brazil is acting according to WTO language about breaking patents in case of a public health crisis. But you have to wonder

Allowing Brazil to use the "public health crisis" justification creates a dangerous and perverse incentive for governments of the developing world: if you as a government are responsible and work hard to uphold a fiscally manageable public health program, then you will be punished by having to pay for expensive drugs, but if you fail or simply ignore the problem and cry "crisis," then you will be rewarded with permission to trample on intellectual property rights.

I've known some pretty good Brazilian scientists, but the country isn't up to being able to discover and develop its own new ones. (Very few countries are; you can count them on your fingers.) So I've saved my usual justification for last: if Brazil decides to grab an HIV medication that other people discovered, tested, and won approval for, who's going to make the next one for them?

July 5, 2005

"I will soon be graduating with a Masters degree. I have been invited to interview at a major Pharmaceutical company, and have been invited to dinner the night before with the Vice President of Drug Discovery. No one I have asked has any idea of what I should expect for this dinner, or how I should prepare.. . ."

Well, the VP isn't going to spend the meal asking you about name reactions - and if he or she does, then scratch that company off your list. You don't want to work at a place where they make you feel like only the select few ever get past their interviews. You'll get asked a bit about your degree work, and you'll be expected to answer pretty fluently - after all, if you can't give a straight and reasonable answer, who can?

You'll get the standard intro to the company, its research structure, and what sort of job you'll be interviewing for. It wouldn't hurt to do some homework before you show up. Check out the company's web site - don't worry that it's full of happy talk and propaganda, because what corporate web site isn't? But this is where you'll find what's known to the public about the research that's going on at the company. If they're strong in cardiovascular research, for example, it won't hurt if you show that you took the time to learn that. That'll give you an opening to ask a question, too, if you want: ("Is this position in the cardiovascular group?")

Other questions that are good to ask (and will help fill up the time, without any awkward gaps) might be: what the area is like to live in, what the mix of people is like in the department (experienced/younger), how often people switch on to new projects, if the person interviewing you has ever worked on anything that made it all the way through the clinic, and so on.

Mostly, these dinners are to make sure that a candidate can hold up their end of a conversation and appears appropriately intelligent. Order something good, and don't worry about having an appetizer and/or dessert. I wouldn't advise drinking any alcohol, though, just to be on the safe side. You should just try to be reasonably pleasant company, and act as if you have a clue about chemistry and research. (Hey, if you've been reading this site for a while, you should at least be able to fake it convincingly. . .)

July 3, 2005

Last year's Fourth of July entry is so much like what we've been up to this year that I'm going to run it as is. Well, instead of a pork shoulder, I did two racks of ribs this time, with branches from a shagbark hickory at the back of my property tossed onto the coals for flavor. But we've made strawberry ice cream again, with berries we picked that morning, and the kids are splashing in the same inflatable pool by the picnic table. I remain just as happy with my family and my life in the country I live in, and I'm just as determined not to lose sight of what got us here:

July 4th here: my two small children are splashing around in an inflatable pool out in the yard while I check the whole pork shoulder that's been cooking since about seven in the morning. More soaked hickory chips go in. (Where I grew up on the Delta, you can spot the barbecue restaurants because they always look as if they're on fire.) I'll have it with beans and my wife's cole slaw, and there's watermelon and homemade strawberry ice cream for dessert.

My wife and her mother are drinking tea out under an oak tree, beyond the kids's splash radius. Next to them, on a green picnic table, I've set up my old microscope, a medical student model that my parents gave me when I was ten. Earlier we were looking at some pond droplets, my son and daughter dripping with pool water as they peered at rotifers and nematodes.

My son has already announced that he wants some scissors when we go back inside, because he wants to cut some of the signatures out to keep from the newpaper's annual full-page reproduction of the Declaration of Independence. He and his sister especially like John Hancock's, of course, and the smart remark he made when he signed it. This year I pointed out Ben Franklin's signature, and related his line about all hanging together or all hanging separately, but I could tell that it didn't register - as it well shouldn't, but I couldn't resist.

They haven't grasped that people back then fought under terrible conditions - aren't they all - to be rid of a king and what he represented. And they don't realize how strange it was for a people to throw off the rule of a king and then, somehow, to avoid ending up under his replacement. (Meet the new boss!) George Orwell famously said that if you wanted to imagine the future, to picture a boot stamping on a human face, forever. But that's an even better summary of the past. Just look at it.

What's even stranger is that for over two hundred years we've continued to avoid all the kings, emperors, sultans, First Citizens, mullahs, all the other graspers and grabbers who long to be at the thick end of the whip. They're in long supply, unfortunately. My wife and her mother, out there in the yard, are both exiles from Iran. They can tell you all about it, starting in the days of the Shah. Then they'll go on to the days after the Shah's portraits were crowbarred down and another loser's stuck right up on the same spot so the paint job wouldn't look funny.

It's safe to say that none of us here in the back yard have any desire to be part of a restored Caliphate. The fellows who want to be in charge of it don't look like the sort who would look kindly on this scene, and not just because of the pork shoulder. And there are plenty of others who would find it necessary to shape things up around here if they were in charge, for that matter.

That'll serve as a test, then: anyone who'll leave us to our own devices this July Fourth - those people are the ones welcome here, strangely enough. If you don't give a damn, then sit down and have some strawberry ice cream. But if you think it's your duty to set us straight, then I've got a section of the newspaper for you to study. It has some holes cut out of the bottom part, but the main points are still there.